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Background: Several studies suggest that vasovagal syncope has a genetic origin, but this is unclear. We assessed whether plausible gene variants associate with vasovagal syncope., Methods: We studied 160 subjects in 9 kindreds comprising 82 fainters and 78 controls. The diagnosis was ascertained with the Calgary Syncope Score. Common genetic variants were genotyped for 12 genes for vascular signaling, potassium channels, the HTR1A(serotonin 5-HT1A receptor), SLC6A4(serotonin reuptake transporter), and COMT(catecholamine O-methyltransferase). Sex-specific associations between genotypes and phenotypes were tested., Results: In 9 out of 12 variants, there was no significant association between genotype and phenotype. However, the HTR1A(-1019) G alleles associated with syncope in males, but not in females ( P=0.005). CC and GG males had 9% versus 77% likelihoods of syncope. The SLC6A4 promoter L alleles associated with decreased syncope in males but increased in females ( P=0.059). The LL and SS males had 25% and 47% syncope likelihoods, whereas females had 75% and 50% syncope likelihoods. The COMT c.472 A alleles associated with decreased syncope in males but increased in females ( P=0.017). The GG and AA males had 50% and 15% syncope likelihoods, whereas females had 52% and 73% syncope likelihoods., Conclusions: There is a sex-dependent effect of alleles of serotonin signaling and vasovagal syncope, supporting the serotonin hypothesis of the physiology of vasovagal syncope.

Background: Adenosine may play a role in the pathogenesis of vasovagal syncope (VVS). The aim of the study was to evaluate the adenosine A(2A) receptor gene 1083 T > C polymorphism in patients with syncope and its possible association with results of head-up tilt test (HUT)., Methods: Three hundred and forty-seven consecutive patients (mean age 47.3 ± 18.5 years, 132 men, 215 women) with one or more syncopal episodes underwent HUT as part of standardized diagnostic evaluation. HUT was positive in 207 patients (75 males, mean age 44.7 ± 18.6 years) and negative in 140 patients (58 males, mean age 48.17 ± 18.8 years). One thousand and eighty-three T > C single nucleotide polymorphism in the adenosine A(2A) receptor gene (rs5751876) was evaluated in 347 patients with syncope and in 85 subjects without history of syncope (54 men, mean age 41.7 ± 16.3)., Results: Adenosine A(2A) receptor 1083 T > C polymorphism was not associated with the positivity of HUT. Blood pressure and heart rate response to tilting was similar in all genotypes. Low frequency (LF) power was significantly lower in CC genotype compared to CT genotype in early phase of tilt (log LF 2.69 ± 0.61 vs 3.20 ± 0.60; P = 0.01) and at the time of syncope (log LF 2.60 ± 0.63 vs 2.77 ± 0.48; P = 0.04)., Conclusions: Adenosine A(2A) receptor 1083 T > C polymorphism is not associated with the positivity of HUT and its proposed role in predisposition to VVS was not confirmed. CC genotype may be associated with lower sympathetic activity during HUT., (© 2015 Wiley Periodicals, Inc.)

Background: Vasovagal syncope is a common clinical condition, consequential to reduced cerebral blood flow resulting from a failure in cardiovascular homeostasis during orthostasis. Blood pressure regulation is the basis for syncope development. In this regulation, the α1a-adrenergic receptor plays a major role. Some studies have found a positive correlation between the Arg347Cys polymorphism of the α1a-adrenergic receptor to hypertension and heart autonomic control. The goal of this study is to evaluate the possible association between the Arg347Cys α1a-adrenergic receptor polymorphism and vasovagal syncope in a Mexican population., Methods/major Findings: A sample of 89 vasovagal syncope patients and 40 healthy controls were studied. Arg347Cys α1a-adrenergic receptor polymorphism was determined by the PCR-RFLP method. We found an increased frequency of genotype ArgArg in vasovagal syncope patients. In a logistic regression model significant associations were found in two genetic models, in codominant model (OR=13.21: CI 95% 3.69-54.99, p<0.001) and in additive model (OR=12.68: CI 95% 3.5-53.07, p<0.001) for ArgArg genotype with CysCys as reference., Conclusions: Our data suggests an important participation of Arg347Cys polymorphism as susceptibility factor in patients with vasovagal syncope. ArgArg genotype could be a marker for vasovagal syncope susceptibility in the Mexican population., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Reflex syncope is defined by a self-terminating transient loss of consciousness associated with an exaggerated response of the vagal reflexes upon orthostatic challenges. A hereditary component has previously been suggested. We hypothesized that variations in genes encoding proteins mediating the vagal signaling in the heart may be involved in reflex syncope pathogenesis. We systematically resequenced the entire coding regions and flanking intron sequences in 5 genes in the cardiac post-synaptic parasympathetic signaling pathway [muscarinic acetylcholine receptor M2 (CHRM2); G-protein beta-1 subunit (GNB1); G-protein gamma-2 subunit (GNG2); potassium inwardly rectifying channel, subfamily J, member 3 (KCNJ3); and potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5)] in 74 patients with well-characterized reflex syncope of either cardioinhibitory [Vasovagal Syncope International Study (VASIS-IIB), N = 38] or vasodepressor (VASIS-III, N = 36) type. We identified 2 novel genetic variants (CHRM2 c.1114C>G and GNG2 c.87+34G>A) and several known variants (GNB1: c.267+14G>A, c.267+19C>T, and c.738C>T; KCNJ3: c.119A>G, c.591C>T, c.1038T>C, and c.1494T>C; KCNJ5: c. 171T>C, c.810T>G, c.834T>C, c.844C>G, c.938+7C>T, and c.938-10G>A). The minor allele frequency of the KCNJ5 c.938+7C>T variant was significantly lower in patients than in the control group (0.014 versus 0.089, P = 0.001), and the frequency of heterozygosity and homozygosity was lower in cardioinhibitory patients compared to controls. Genetic variations in genes responsible for the vagal signaling in the heart, including CHRM2, GNB1, GNG2, KCNJ3, and KCNJ5, are not major contributors to the pathogenesis of reflex syncope of vasodepressor or cardioinhibitory types.

Although the pathophysiology of vasovagal syncope is not completely understood, the involvement of sympathetic nervous system alterations has been suggested. Since predisposition to fainting during orthostatic challenge may be associated with genetic variations, we sought to explore the role of genetic polymorphisms affecting sympathetic nervous system function in the susceptibility to tilt-induced vasovagal syncope. We genotyped 129 subjects with recurrent unexplained syncope who underwent tilt testing, and investigated the recurrence of syncope. The analysed polymorphisms were Arg492Cys (ADRA1A gene), Ser49Gly and Arg389Gly (ADRB1), Arg16Gly and Gln27Glu (ADRB2), 825C/T (GNB3), -1021C/T (DBH) and S/L (SLC6A4). No association of the aforementioned genetic variants with both tilt test outcomes and new syncopal episodes during follow-up was found. None of the considered polymorphisms influencing sympathetic activity is a major risk factor for vasovagal syncope in Italian patients., (.)